Rheumatic fever

Author: Dr Catherine Weil-Olivier1

Creation Date: March 2003
Update:
January 2004
Scientific Editor: Dr Frank Dressler
1

Hpital Louis Mourier, 178, rue Renouillers, 92700 Colombes, France.

c.weilolivier@lmr.ap-hop-paris.fr

Abstract
Keywords
Disease name and synonyms
Excluded diseases
Diagnostic criteria/definition
Differential diagnosis
Prevalence
Clinical description
Management including treatment
Diagnostic methods
Genetic counseling
Antenatal diagnosis
References
Abstract
Rheumatic fever (RF) is a multisystem inflammatory disease, which occurs as a delayed sequel to group
A streptococcal pharyngitis. It may involve connective tissues of the heart, joints, skin and vessels. In
developing countries, rheumatic fever is endemic and remains one the major causes of acquired
cardiovascular disease. It is a major cause of mortality among subjects under 50 years of age and its
annual incidence is 100-200 times greater than that observed in industrialized countries. Migratory
polyarthritis with fever is frequently the initial sign. Arthritis is only present in 75% of patients. The most
commonly affected joints are the knees, ankles, elbows, wrists and, far more rarely, the hips and small
joints of hands and feet. The migratory character of the arthritis and the intensity of the pain are
suggestive of RF, and these features are not consistently bilateral and symmetrical. Carditis occurs early
(within 3 weeks of onset) and inconsistently: it is seen in 50% of cases on clinical examination and in 70%
of cases by echocardiography. The carditis may appear during any bout of the disease. Endocarditis is
always present and may be the most serious sequela to GABHS (Group A beta haemolytic streptococcal)
infection, leading to permanent rheumatic heart disease. Treatment of RF depends on the
symptomatology. Fever and joint pain/swelling are usually treated with aspirin. All patients should be
treated with a ten-day course of penicillin (or alternative antibiotic in cases of allergy to penicillin).
Prophylactic antibiotics to prevent further GABHS infections, which may cause a recurrence of symptoms,
should be prescribed. The antibiotic treatment consists of intramuscular injection of penicillin every 3-4
weeks or bi-daily penicillin tablets. Other antibiotics are sometimes required. Antibiotics should be
continued at least up to adulthood for children without carditis and for life in patients with carditis
Keywords
Rheumatic fever, GABHS, penicillin, pharyngitis

Disease name and synonyms

Rheumatic fever (RF)
Acute articular rheumatism

Diagnostic Criteria/ Definition

RF is a multisystem inflammatory disease that
occurs as a delayed sequel to group A

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streptococcal pharyngitis. It may involve

connective tissues of the heart, joints, skin and
vessels.
The clinical features of acute RF are described
under Jones criteria (table 1), which were first
established in the 1940s and updated in 1992 (16). These criteria are used at the acute stage of
the disease; patients meeting these criteria are

highly likely to have RF. The diagnosis is clinical

in the absence of any pathognomonic laboratory
test. RF criteria do not exclude other causes of
febrile polyarthritis, which need to be considered.
In the absence of any other explanation, the
diagnosis of RF may be maintained, even if the
symptoms are incomplete.

Table 1: Jones criteria for the diagnosis of Rheumatic Fever (6)

Criterion
Major
Minor
Carditis
Polyarthritis
Fever
Clinical
Chorea
Arthralgia
Erythema marginatum
Subcutaneous nodules
Elevated acute-phase reactants (ESR, CRP) Prolonged PR interval (ECG)
Evidence of antecedent group A streptococcal infection:
Laboratory
positive culture for GABHS*,
elevated or rising streptococcal antibody titer
The diagnosis of rheumatic fever is highly suggested when two major criteria or one major and two minor criteria are
fulfilled in a patient with previous streptococcal infection
*GABHS: Group A beta haemolytic streptococcus

Epidemiology
The spectacular evolution of RF over the years
is surprising. The frequency of the disease was
very high at the beginning of the 20th century
(100-200 cases per 100,000 in the US
population in 1900 and 50 per100,000 in 1940).
RF was a major cause of mortality in children
and adolescents and a common cause of heart
disease in young adults. Until the early 1980s
there was a steep decline to about 0.5 per
100,000 in the USA. Since then, there have
been several localized outbreaks of RF. In
Europe, there have been similar declines in the
overall incidence of RF, and it has become a
rare disease. The incidence of RF varies greatly
between countries (Table 2). In developing
countries, RF is endemic and remains the major
cause of acquired cardiovascular disease. It is
also a major cause of mortality in subjects under
50 years of age, and the annual incidence of RF
is 100-200 times greater than that observed in
industrialized countries. RF usually occurs in
patients between 5 and 15 years of age. It is
rare before the age of 3 years and 92% of cases
occur until the age of 18 years.
RF is a complication of GABHS infection in a
predisposed human host. Fewer than 2 to 3% of
previously healthy persons develop RF following
GABHS pharyngitis. RF does not occur after
streptococcal pyoderma.
Clinical description
Given the current rarity of the disease and the
absence of established laboratory criteria, the
diagnosis of RF is based on clinical criteria and
may be difficult to establish. However, late
diagnosis is prejudicial since a bout of RF is a
therapeutic emergency.

Polyarthritis with fever is still the initial warning

sign. Arthritis is the most common major
manifestation of RF, but only present in 75% of
patients. The most commonly affected joints are
the knees, ankles, elbows, and wrists and, far
more rarely, the hips and the small joints of
hands and feet. The migratory character of the
arthritis and the intensity of the pain are
suggestive of RF, and these features are not
consistently bilateral and symmetrical.
Carditis is the most serious manifestation of RF
and occurs early (within 3 weeks of onset). It is
seen in 50% of cases on clinical examination,
and in 70% of cases by echocardiography.
Clinically, rheumatic carditis is almost always
associated with a murmur of valvulitis, most
commonl the apical systolic murmur of mitral
regurgitation and/or the basal diastolic murmur
of aortic regurgitation. Suspected valvulitis
should
be
evaluated
promptly
by
echocardiography. Carditis may appear during
any bout of the disease. It is an inflammatory
pancarditis
affecting
endo-,
myoand
pericardium. Endocarditis is almost always
present and is the most serious sequela to
GABHS (Group A beta haemolytic streptococcal)
infection, leading frequently to permanent
rheumatic heart disease. Myocardial disease is
inconsistent and may range from congestive
heart failure, which is rarely life threatening, to
more frequent disorders of atrioventricular
conduction. The classic lengthening of the PR
interval is one of the minor Jones criteria.
Electrocardiography should be carried out in all
patients. Pericarditis is rare (< 5%). Myocarditis
and pericarditis once cured do not leave
sequelae.
Sydenham's chorea (SC) is a delayed
manifestation (1 to 6 months) of GABHS

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infection typically associated with RF. It is

characterized
by
sudden,
involuntary,
arrhythmic, clonic, and purposeless movements
resulting from an autoimmune attack on the
CNS. In addition to chorea, the acute attack is
almost always characterized by psychiatric
symptoms such as irritability, obsessions and
compulsions, tics, and psychotic symptoms.
Diagnosis of SC is more complicated due to the
lower frequency of elevated streptococcal
antibodies and acute-phase reactants in patients
with SC than that found in patients with acute RF
presenting with arthritis or carditis. Motor
symptoms observed in patients with SC include
ballismus, facial grimacing, gross fasciculations
of the tongue, loss of fine motor control,
hypotonia,
motor
impersistence,
gait
disturbance, and speech abnormalities such as
dysarthria and explosive speech. Chorea occurs
most commonly between the ages of 7 and 14
years with the peak incidence at 8 years. It is
rare after puberty and exceedingly uncommon
after the age of 20 years. In the 1950's chorea
occurred in approximately 50% of cases of acute
RF. The incidence has declined substantially
with chorea now being a component of less than
10% of cases of acute RF.
The quasi-pathognomonic skin signs (erythema
marginatum and subcutaneous nodules) are rare
and more frequently observed when there is
cardiac involvement. Compared to arthritis,
carditis
and
erythema
marginatum,
subcutaneous nodules occur late in the course
of RF. A rash similar to that seen in scarlet fever
is possible, reflecting recent streptoccocal
infection.
Table 2: Differences in the incidence of rheumatic fever
between countries (6-12)
Incidence of RF in the children
Country
and adolescents
Martinique
20/100,000
Guadeloupe
17/100,000
Egypt
10/100,000
Thailand
1.2-2.1/100,000
India
1.8-11/100,000
USA
0.23-1.88/100,000
Japan
0.23-1.88/100,000
Denmark
0.23-1.88/100,000
Great Britain
0.23-1.88/100,000
Australia
0.23-1.88/100,000
France
0.08-0.15/100,000

Etiology
Pathogenesis
Cheadle reported the association between a
throat infection and RF in 1889 (13). As early as
1900, several authors pointed out the role of
Streptococcus and the proliferative and nonsuppurative character of RF. The introduction of
antibiotics, sulphonamides and then penicillin, in

the 1940s demonstrated that penicillin treatment

for streptococcal pharyngitis had a preventive
effect against RF (14,15).
The microorganism action is mediated by its
virulence factors (7,11,16,17). The appearance
of toxic shock syndrome and the stable number
of glomerulonephritis and sore throat cases in
industrialized countries, suggests that the
evolution of these factors in specific strains
accounts for the epidemic outbreaks of RF in the
USA, and its persistence in France as a sporadic
infection.
As a result of the many findings accumulated
over the last 100 years, the relationship between
GABHS pharyngitis and the development of RF
is now universally recognized. Effective
treatment
of
GABHS
tonsillopharyngitis
prevents RF. However it has been demonstrated
that GABHS remains present in the throat even
after adequate treatment in about 10% of cases.
The close link between Streptococcus pyogenes
and RF is well established, but the precise
pathogenesis of RF and rheumatic heart is not
fully understood. Correlation between the
cardiac manifestations and the autoimmune
response has been established (9,18).This
autoimmune response is very important and
could be detailed (more than predisposition) :
refer to the main article for that.
Predisposition
The importance of individual host factors in RF
has been suspected for more then a century
(19). The first disease reports highlighted a
frequent predisposition to RF, but a specific
genetic profile or Mendelian transmission of the
disease have never been demonstrated. The
discovery of specific HLA antigens within the
context of various autoimmune diseases led to
an intensive search for such antigens in RF.
Ayoub et al (20) were the first to demonstrate an
increased frequency of HLA-DR4 in white RF
patients and HLA-DR2 in black RF patients.
Although this remains true in Utah and Turkey,
associations with other HLA types have been
found in other countries in subjects with
rheumatic heart disease. Examples include DRA
and DRw6 in black African patients in South
Africa; DR7 and Dw53 in Brazil; DQw2 in India;
HLA-B17,
HLA-B21
and
HLA-Cw4
in
Uzbekistan. The marked variability of dominant
HLA antigens in different populations suggests
that their close association with the disease is
unlikely.
Alloantigens, which are expressed at the surface
of lymphocytes and recognized by monoclonal
antibodies, appear to be markers of that
susceptibility, especially when there is cardiac
involvement (found in 75-90% of cases). These
alloantigens appear to be expressed only after
stimulation by GABHS antigen (19).

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Diagnostic Methods
When investigating a febrile patient with
polyarthritis, the erythrocyte sedimentation rate
(ESR) should be measured in priority. ESR is
usually >80; with an initial ESR of <60, the
diagnosis of RF is less likely and this rate is
more compatible with a post-streptococcal
syndrome (21). The other laboratory tests
contribute to the diagnosis retrospectively:
positive throat culture of GABHS is inconsistent
and the absence of a positive culture does not
exclude the diagnosis. It is advisable to also take
throat swabs from the immediate family and, if
GABHS are found, to carry out serotyping. Tests
for various antibodies (antistreptolysin O
antibody (ASLO) and anti-Dnase B (ASDB))
where necessary, are of limited diagnostic value
(20% of cases of RF are not accompanied by
raised antibody levels).
Management including treatment and
outcome
The therapeutic management of the disease has
three main goals: first, the eradication of
GABHS, second an anti-inflammatory treatment
of the symptoms of RF and third long term
prophylaxis of recurrent infection Table 3
describes the antibiotic and anti-inflammatory

measures required. The anti-inflammatory

treatment is longer in case of steroid
dependence. Intramuscular penicillin is the most
reliable administration route, provided that the
injections
are
given
every
3
weeks.
Intramuscular penicillin is the most reliable
administration route, provided that the injections
are given every 3 weeks.
For an initial bout of RF, the prognosis is good,
except for the rare deaths due to heart failure.
Correct prophylaxis prevents recurrences,
stressing the importance of satisfactory
compliance with the preventive anti-infective
treatment. Relapses are more frequent in the
first 3-5 years following the first episode.
Each bout is associated with a risk of cardiac
involvement and the existence of cardiac
disorders (i.e carditis) in the initial phases
increases this risk.
The severity of RF lies entirely in the cardiac
sequelae, which are mainly mitral and
sometimes
aortic
valve
disease.
Echocardiography must be carried out on these
patients every 6 months; usually there is
attenuation of the lesion during the first 2 years.
All children who have suffered cardiac sequelae
must be thoroughly instructed on risk prevention
of bacterial endocarditis.

Table 3: Principles of therapeutic management

I- Antibiotic regimens
Antibiotic
Eradication regimen
Secondary prophylaxis
Benzathine penicillin im*
1.2 MIU** every 3-4 weeks
Bodyweight <27kg
600,000 IU x 1
Bodyweight >27kg
1.2 MIU x 1
100,000 IU/kg/day for 10 days
20,00-300,000 IU/kg/day
Penicillin V, oral
750 mg in 3 doses/day
500 mg in 2 doses/day
Erythromycin
40mg/kg/day in 3 doses/day
500 mg in 2 doses/day
Duration of treatment: if no carditis : five years long, up to adolescence ; if one episode of carditis : life long
II- Anti-inflammatory treatment

Carditis
Severe carditis present
Mild to moderate carditis

Anti-inflammatory agent
Corticosteroids
Aspirin
Prednisolone 2mg/kg/day< 80 mg /day
start aspirin 1 week before termination of steroids
1 dose/day for 3-4 weeks decreasing over 6-8 weeks
80-100 mg/kg/day4 doses/day for 4-8 weeks
Not essential
Decreasing over the following 4 weeks

*im: intramuscular
**MIU: million international units

Conclusions
Understanding the significance of infection
sequelae is crucial when approximately 238
million cases in the world of pharyngitis are
diagnosed annually on the basis of the number
of antibiotics prescriptions in children and adults.
GABHS plays a limited role in the etiology of
sore throat, being present in only about 20% of
cases. The introduction of simple tests for the
rapid diagnosis of GABHS could allow a more
rational approach to the treatment of pharyngitis
with improved targeting of antibiotic therapy. An

additional strategy may be the use of antibiotics

other than penicillin, possibly for a shorter period
(5 days) in order to increase compliance with
treatment. The combined strategies, rapid tests
for GABHS and short-duration treatments, have
proved as efficacious as penicillin without
evidence of a rise in the incidence of RF (22).
RF is now a rare disease in most of Europe and
North America, making its diagnosis more
difficult. Initial treatment is well defined but poor
compliance with preventive treatment carries the
risk of cardiac disease, which can sometimes be
severe.

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It is very difficult to predict evolution in the

coming years. It is not clear whether the
epidemic outbreaks or the rare observed cases
are aberrations in the generally declining profile
currently observed in developed countries, or if
there is a true risk of resurgence of the disease.
Consequently, accurate identification of GABHS
sore throats and follow-up of rheumatogenic
strains together with their appropriate treatment
is still important.
Unresolved questions
RF still poses many questions (23-26).
Does the disease still exist and what is its
epidemiology?
How can we understand its pathogenesis?
Have its clinical expression and out come
changed and how should we manage the
treatment of sore throat in the future?
Despite
the
considerable
advances
in
understanding of the molecular biology of S
pyogenes and the interrelations of the
autoimmune
response
between
the
microorganism and the host, the precise
pathogenesis of rheumatic heart disease is not
fully understood.
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4th
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Philadelphia, 2001 ; pp. 690-705.
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Weil-Olivier C.; Rheumatic fever. Orphanet encyclopedia, January 2004.

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